RIBOTAC-mediated degradation of hsa-microRNA-301a-3p suppresses TNBC bone metastasis.

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype with a high propensity for bone metastasis and limited treatment options. Although many proteins drive metastasis, most remain inaccessible to conventional small-molecule drugs due to lack of suitable binding sites, prompting interest in upstream RNA regulators. Using integrative bioinformatics and machine learning, we identified hsa-microRNA-301a-3p as a central regulator of TNBC bone metastasis. However, current nucleic acid-based therapies are limited by instability and inefficient delivery. To overcome these challenges, we designed a ribonuclease-targeting chimera (RIBOTAC) that recruits endogenous RNase L to degrade the primary transcript pri-microRNA-301a. The resulting RIBOTAC efficiently reduced hsa-microRNA-301a-3p levels, restored NEDD4L expression, and promoted degradation of the oncogenic protein YAP, thereby suppressing TNBC bone metastasis. These findings identify hsa-microRNA-301a-3p as a key driver and demonstrate RNA-targeted degradation as a therapeutic strategy in TNBC bone metastasis.